High-Throughput Drug Stability Assessment via Biomimetic Metalloporphyrin-Catalyzed Reactions Using Laser-Assisted Rapid Evaporative Ionization Mass Spectrometry (LA-REIMS).

Background: Building extensive drug candidate libraries as early in the development pipeline as possible, with high-throughput in vitro absorption, distribution, metabolism, and excretion (ADME) profiling, is crucial for the selection of lead compounds to guide subsequent research and production phases. Traditionally, the analysis of metabolic stability assays heavily relies on high-throughput LC-MS/MS (liquid chromatography tandem mass spectrometry) techniques to meet with the lead profiling demands. Laser-assisted rapid evaporative ionization mass spectrometry (LA-REIMS) is a quick and efficient technique for characterizing complex biological samples without laborious sample preparation. Objective: In this study, using an automated LA-REIMS well plate reader, achieving an 8 s per sample measurement time, the oxidative metabolic stability of active drug agents was assessed using biomimetic metalloporphyrin-based oxidative model reactions. Results: The results obtained using the novel LA-REIMS-based protocol were compared to and corroborated by those obtained using conventional HPLC-UV-MS (high performance liquid chromatography with ultra-violet detection coupled with mass spectrometry) measurements. Conclusions: LA-REIMS emerges as a promising technique, demonstrating potential suitability for semi-quantitative high-throughput metabolic stability in an optimized solvent environment.